Genomics of MTAP Loss in >500,000 Solid Tumor Specimens Profiled Using Comprehensive Genomic Profiling Platforms.

PURPOSE: Methylthioadenosine phosphorylase (MTAP) genomic loss is an emerging biomarker for PRMT5 and MAT2A inhibitors based on synthetic lethality. The MTAP gene is located on chromosome 9p21.3 near CDKN2A/B. MTAP homozygous loss across tumor types, specific exons lost, MTAP expression, and the landscape of coalterations were assessed.

METHODS

409,755 tissue biopsies (TBx) and 85,801 liquid biopsies (LBx) were sequenced using hybrid capture-based NGS (FoundationOne CDx or FoundationOne Liquid CDx), evaluating all classes of genomic alterations and circulating tumor DNA (ctDNA) tumor fraction (TF). Additionally, 6,740 TBx were subjected to both RNA and DNA sequencing to compare MTAP gene expression with genomic MTAPloss.

RESULTS

The prevalence of pan-tumor MTAPloss was 11.4% using TBx, with the highest prevalence observed in mesothelioma (32.8%), glioma (32.7%), pancreatic (28.9%), and bladder cancers (26.4%). Prevalence of MTAPloss on LBx approximated that of TBx when ctDNA TF ≥20% (positive percent agreement [PPA] = 86.2%). CDKN2Aloss was not a reliable proxy for MTAPloss; 33.7% of CDKN2Aloss cases did not have MTAPloss. MTAPloss was enriched with CDKN2A/B losses pan-tumor, EGFR in NSCLC, ERBB2 in colorectal cancer, and PTEN in prostate cancer, while MTAPno_loss was enriched for RB1 pan-tumor, APC in colorectal cancer, CCNE1 in breast and ovarian cancer, and SPOP in prostate cancer. Complete loss (exons 1-8) was observed in 82.9%, multiple exons in 16.5% and exon 8 alone in <1%. MTAPloss, specifically the number of exons lost, was correlated with reduced RNA expression.

CONCLUSION

MTAPloss is a frequent pan-tumor alteration that predicts potential sensitivity to PRMT5 or MAT2A inhibitors. Although most tumors exhibit complete MTAPloss, 16.5% are characterized by partial MTAPloss where clinical benefit remains uncertain. The genomic coalteration landscape reported here may inform future PRMT5 or MAT2A clinical trials, potentially in combination with other agents.